The Science of Aging: Where We Are and Where We Could Go
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This document discusses the science of aging and challenges in aging research. It defines aging as the progressive decline in physiological function over time due to genetic and environmental factors. The document summarizes current understanding of aging mechanisms like DNA damage, protein misfolding, stem cell depletion, cellular senescence, and chronic inflammation. It also outlines the landscape of aging research including current funding levels and companies developing therapies. Major challenges discussed are the complexity of aging, difficulty capturing treatment value, and need for results in aged biological systems. The document advocates scaling therapeutic discovery through parallel in vivo testing in animal models of aging.
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The Science of Aging: Where We Are and Where We Could Go
- 1. The Science of Aging Where we are and where we could go Martin Borch Jensen Fifty Years HQ November 18, 2019
- 3. According to NIH grant review panels: Experience: Who am I? Nanobiotechnology M.Sc Ph.D. DNA repair Accelerated aging Mitochondria Inflammation/signaling K99
- 4. Aging as a problem Defining ‘aging’ Mechanisms of aging Landscape & challenges
- 5. c c Aging is a growing challenge c c German census & projection
- 6. Aging is the ultimate risk factor 10 200 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 Age / years Diseaseincidence/% Cancer Cardiovascular Dementia Diabetes $88B $318B $259B $176B Direct costs (USA)
- 7. S m o kin g D iet S ed entary lifestyle O ccu p atio n al exp o su re F a m ily h isto ry V iru se s Perin atal A lco h o l S o cio eco n o m ic statu s Po llu tio n U V radiatio n D ru gs & M ed ical p ro ce d u res S alt & fo o d ad d itives Risk factors for cancer Aging is the ultimate risk factor More accurate risk factors for cancer Aging
- 8. NIH research funding Cancer Heart/lung/blood $5.1B $3B Diabetes & Kidney $2B Neuro/ Stroke $1.6B Aging $1.2B Alzheimer’s $13BAge-associated diseases ≈5% Aging research is not being funded Numbers from 2017
- 9. US healthcare spending (≈$4T) NIH research spending Total disease spending Aging research is not being funded x3→ Numbers from 2017
- 10. Early investments haven’t paid off Why isn’t aging research funded?
- 11. Why isn’t aging research funded?
- 12. Is anything different now? Why isn’t aging research funded?
- 13. Life extension in daf-2 mutant worms Kenyon et al., Science, 1993 Single genes can alter aging rates
- 14. Mouse 2-3 years Bat 20 years Naked mole rat 28 years Biodiversity of aging
- 15. Turritopsis dohrnii T. dohrnii life cycle Aging is reversible
- 16. Aging is reversible (in humans?)
- 17. Aging as a problem Defining ‘aging’ Mechanisms of aging Landscape & challenges
- 18. How to think about “aging”
- 19. Solanas & Benitah, Nat. Rev. Mol. Cell Biol. 2013 Not visible signs of aging…. …but underlying processes Causes rather than symptoms
- 20. Aging versus disease Martinez et al., Nat. Rev. Dis. Primers 2017 Various types of injury (smoke, infection, …) kills epithelial cells Aberrant attempts at repair cause fibrosis • Cells more vulnerable to injury, increased cell death. • Decreased stem cell function reduces regeneration. • Chronic inflammation increases fibrotic response. • Dysfunctional fibroblasts remain active and fail to clear scar tissue. Age-related contributors Progression of idiopathic pulmonary fibrosis
- 21. Aging is the gradient of morbidity 10 200 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 Age / years Diseaseincidence/%
- 22. Not extending sick state… …but slowing deterioration, stretching healthy lifespan SickHealthy Healthspan and lifespan
- 23. Defining “Aging” Systemic & progressive decline in ability to preserve physiological function in the face of genetic and environmental challenges.
- 24. Single-cause theories losing support Lopez-Otin et al., Cell 2013Neal Fedarko A 1956 view of aging
- 25. How do we study aging? • Study the mechanism. • Measure lifespan. • Accelerated lifespan, in simplified systems. • Start with aged, try to reverse it.
- 26. How do we study aging? • Study the mechanism. • Measure lifespan. • Accelerated lifespan, in simplified systems. • Start with aged, try to reverse it.
- 27. How do we study aging? • Study the mechanism. • Measure lifespan. • Accelerated lifespan, in simplified systems. • Start with aged, try to reverse it.
- 28. Biology is universal (with porting challenges) Yeast Mammals
- 29. Biology is universal (with porting challenges)
- 30. [Intermission]
- 31. Aging as a problem Defining ‘aging’ Mechanisms of aging Landscape & challenges
- 32. Organismal Cellular DNA/RNA Proteins Metabolism Tissues Stem cells Intercellular signaling Things that break with age
- 33. McLeod et al., Biogerontology, 2016 Male, 24 years Male, 66 years Male, 66 years Physically active Sarcopenia/Muscle loss Tissues lose functional cells with age
- 34. Tissues lose functional cells with age Replacement of your thymus with fat happens early in puberty/adulthood Thymus at 2 months Thymus at 24 years Mestanova & Varga, Biologica, 2016
- 35. Adapted from Akunuru & Geiger, Trends Mol. Med. 2015 Imbalanced cellular populations with age Blood cell imbalance causes immune dysfunction Aging
- 37. One genome, different organs?
- 38. moderate high very low Gene 1 2 3 … Cellular programs run off DNA
- 39. DNA RNA DNA damage causes loss of information A U G C A C A G U G U C A U C Ile Gln Cys HisMet His Ser Val Ile
- 40. ~23,000 genes 13 genes Nuclear Mitochondrial DNA exists in two parts of the cell
- 41. Trifunovic et al., Nature 2004 Mitochondrial DNA mutations accelerate aging Mitochondrial ‘mutator mouse’ ‘Mutator mouse’ has short lifespan
- 42. Telomeres MAY limit lifespan
- 43. Mortality correlates with short telomeres Cawton et al., Lancet 2003 Telomeres MAY limit lifespan Short telomeres cause: DNA damage response Cellular senescence Disrupted metabolism Lazzerini-Denchi & Sfeir, Nat. Rev. Mol. Cell Biol. 2016
- 44. Chromatin packing is lost with age Oberdoerffer & Sinclair, Nat. Rev. Mol. Cell Biol. 2007 Hutchinson-Gilford Progeria Syndrome
- 46. Protein activity affects everything
- 47. Proteins must fold correctly Translation Chaperone-mediated folding Functional protein
- 48. Lopez-Otin et al., Cell 2013 Misfolded proteins are damaging Protein cleanup mechanisms
- 49. NeuroPhage Pharmaceuticals Misfolded proteins are damaging
- 50. Lopez-Otin et al., Cell 2013 Misfolded proteins are damaging Protein cleanup mechanisms
- 51. Simonsen et al., Autophagy 2008 Misfolded proteins limit lifespan Stimulating autophagic protein cleanup extends lifespan Wildtype Wildtype Proteinslabeledfordegradation
- 52. Adapted from Parkinson et al., Aging Cell 2014 Extracellular proteins change with age Aging
- 54. Life extension in daf-2 mutant worms Kenyon et al., Science, 1993 Many ‘aging genes’ regulate metabolism
- 55. Harrison et al., Nature 2009 Manning et al., Sci. Transl. Med. 2018 Regulating growth signaling affects aging Rapamycin treatment in old, outbred mice Rapalogues reduce infections in patients age >65
- 56. Colman et al., Science 2009 Calorie restriction slows aging 30% CR in rhesus monkeys, age 28 years Incidence of age-related disease in CR monkeys
- 57. Intermittent Fasting may too Mitchell et al., Cell Metab. 2018 Ahmet et al., Circulation 2005 Limited feeding time, not calories… …extends lifespan… …and protects against injury.
- 58. Rule of thumb: Abundance causes damage Abundant food & growth signaling Scarce food & protective signaling CR Interventions
- 60. Stem cells exist in most tissues
- 61. Stem cells self-renew upon division Stem cell division Ito & Suda, Nat. Rev. Mol. Cell Biol. 2014
- 62. Stem cell pools deplete with age Aging Ito & Suda, Nat. Rev. Mol. Cell Biol. 2014
- 63. 100 µm Adapted from Fry et al., Nat. Med. 2014 StemcellsdepletedControl Before 7d after injury Stem cell depletion impairs regeneration
- 64. De Los Angeles & Daley, Nature 2013 ‘Stemness’ is a cellular program
- 65. Restoring stem cells may rejuvenate
- 66. Adapted from Childs et al., Nat. Rev. Drug Disc. 2017 Senescence = a different cellular program Senescence-associated secretion of inflammatory, mitogenic and fibrotic signals (SASP) Altered metabolism & resistance to cell death Cell division arrested, persistent DNA damage, short telomeres
- 67. Munoz-Espin & Serrano, Nat. Rev. Mol. Cell Biol. 2014 Senescent cells accumulate with age Normal and aged senescence-associated inflammation
- 68. Baker et al., Nature 2016 Clearing senescent cells improves health Appearance and lifespan of senescence-cleared mice
- 70. Old blood contains pro-aging factors Young serum Adapted from Science 2015 Heterochronic parabiosis
- 71. Villeda et al., Nature Med. 2014 Young blood rejuvenates the brain Increase in dendritic spines Improved learning capacity
- 73. Adapted from Bruunsgaard et al., J. Geront. 1999 Aging increases chronic inflammation Increase in circulating inflammatory factors with age
- 74. Chronic inflammation is bad for you
- 75. Chronic inflammation is bad for you Adapted from artinez et al., Nat. Rev. Dis. Primers 2017 Various types of injury (smoke, infection, …) kills epithelial cells Aberrant attempts at repair cause fibrosis • Cells more vulnerable to injury, increased cell death. • Decreased stem cell function reduces regeneration. • Chronic inflammation increases fibrotic response. • Dysfunctional fibroblasts remain active and fail to clear scar tissue. Age-related contributors Progression of idiopathic pulmonary fibrosis
- 76. Organismal Cellular DNA/RNA Proteins Metabolism Tissues Stem cells Intercellular signaling Aging = systemic decline and decoherence
- 77. [Intermission]
- 78. Aging as a problem Defining ‘aging’ Mechanisms of aging Landscape & challenges
- 81. Aging ecosystem is growing 0 5 10 15 20 25 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 See Karl Pfleger’s http://agingbiotech.info/ for more details. Newaging-focusedbiotechsfoundedbyyear
- 82. Calico ($2.5B) Basic research by former academics. Broadly licensing candidate drugs. Tooling & data science efforts. Including big players Other umbrella companies:
- 83. 1. Hard to capture value 2. Aging takes a lifetime 3. Optimizing a complex system What are the major challenges?
- 85. FDA approves drugs for manifested damage 10 200 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 Age / years Diseaseincidence/% Cancer Cardiovascular Dementia Diabetes YES NO
- 86. & others Senescent cell clearance: Who is developing aging therapeutics?
- 87. & others Stem cells & regenerative: Who is developing aging therapeutics?
- 88. & others mTOR pathway (growth signaling): Who is developing aging therapeutics?
- 89. Factors in young blood: Who is developing aging therapeutics?
- 90. • Osteoarthritis • Lung fibrosis (IPF) • Hair loss • Alzheimer’s disease • Cancers • Degenerative disc dis. • Tendinopathy Go-to-market: Age-related disease (then expand) • Osteoarthritis • Lung fibrosis (IPF/COPD) • Macular degeneration • Diabetic retinopathy • Glaucoma • Chronic kidney disease Indicationspursued • Alzheimer’s disease • Parkinson’s disease • “Age-related disease” • Depression • Chronic kidney disease • Alzheimer’s disease • Parkinson’s disease • Macular degeneration • “Inflammatory disease”
- 91. Example: Unity Biotechnology 2011 Unity founded 2012 2017 2016 Basic science Candidates Disease links
- 92. & many others Direct to consumer: Domestic animals: Avoiding the FDA
- 94. 1. Hard to capture value 2. Aging takes a lifetime 3. Optimizing a complex system What are the major challenges?
- 96. Level 1 Snapshot of biological age, i.e. physiological function and risk of morbidity Level 2 Biological age, based on causative process(es) Level 3 Trajectory of biological age, with causative information (non-destructively) (across experimental systems and patients) Biomarkers of aging
- 97. Biomarkers of aging DNA methylation
- 98. Biomarkers of aging Maegawa et al., Nature Comms. 2017 DNA methylation at specific genes correlate with age
- 99. Biomarkers of aging Maegawa et al., Nature Comms. 2017 Aging interventions seem to affect clock
- 100. Biomarkers of aging DNA methylation MicroscopyBlood metricsInflammation & several smaller (Horvath clock) ( )
- 101. Knowledge Development Treatment Age-related diseases Academia FDA Investors Pharma Founders Biomarkers & toolsFoundations Aging
- 102. 1. Hard to capture value 2. Aging takes a lifetime 3. Optimizing a complex system What are the major challenges?
- 103. Schoenfeld & Iodannis, Am. J. Clin. Nutr. 2012 Cancer risk with high consumption of… “Better” is an elusive goal
- 104. Apoptosis pathway Everything is multifactorial and dynamic
- 105. Simple diseases Test tube (in vitro) experiments predict human outcomes. Disease complexity can only be modeled in aged organisms (in vivo). Diseases of aging We need results in the right context
- 106. The industry has only been able to explore a small fraction of possible targets in each disease. Goal: In vivo efficacy Cost per input target: $17.6M Time to in vivo efficacy: 4.5Yrs Goal: Human safety / efficacy Preclinical drug discovery In vivo testing is customized for a specific gene target. Clinical validation Often the first time testing factors in age. Now: in vivo validation takes a whole company
- 107. Goal: In vivo efficacy Cost per input target: $1k Time to in vivo efficacy: 6mo Need: Test all targets, develop the right ones Gordian tests and ranks thousands of targets in parallel, moving the best to clinical trials Goal: Human safety / efficacy Preclinical drug discoveryPreclinical drug discovery With scaled in vivo testing. Clinical validation
- 108. Scaling therapeutic discovery for diseases of aging Hundreds of different gene therapies Injected into the best animal model Unique interventional data improves following libraries Independent experiments in the diseased environment Measure response of every cell simultaneously
- 109. Knowledge Development Treatment Age-related diseases Academia FDA Investors Pharma Founders Biomarkers & toolsFoundations ? Aging
- 110. Summary • Aging costs society trillions of dollars per year (and sucks). • Human aging is a biologically solvable problem. • We understand many of the factors, but not the whole system. • Linking aging mechanisms to disease is tricky, but rewarding (in health and $) • We need better tools to measure aging and therapeutic efficacy. • There is no cavalry.
- 111. A few ideas • Identify approved drugs extending female fertility via medical records. • Target insulin-sensing pathway using new therapeutic modality. • Create blood-based biomarkers of specific age-related dysfunctions. • Reduce costs for cell and gene therapy, enabling precise interventions. • Business model that incentivizes preventative medicine.
- 112. Thank you! I love helping people learn how to have an impact on aging biology, and tell hype from promising science. Feel free to contact martin@gordian.bio if you have questions.